In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high ...proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance.
•To maintain a high proliferation rate cancer cells adapt their cellular metabolism.•This results in depletion of nutrients and release of toxic metabolites in the tumor microenvironment.•In response to tumor cells-derived metabolic cues TAMs undergo metabolic reprogramming.•Metabolic reprogramming of TAMs subsequently influences their functional phenotype.
Trained Innate Immunity, Epigenetics, and Covid-19 Mantovani, Alberto; Netea, Mihai G
New England journal of medicine/The New England journal of medicine,
09/2020, Volume:
383, Issue:
11
Journal Article
In addition to its specific effect against tuberculosis, the BCG vaccine has beneficial nonspecific (off-target) effects on the immune system that protect against a wide range of other infections and ...are used routinely to treat bladder cancer.1,2 This has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against severe coronavirus disease 2019 (COVID-19). In Guinea-Bissau, a high-mortality setting, BCG-Danish reduced all-cause neonatal mortality by 38% (95% CI 17–54), mainly because there were fewer deaths from pneumonia and sepsis.3 In South Africa, BCG-Danish reduced respiratory tract infections by 73% (95% CI 39–88) in adolescents.4 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded positive-sense RNA virus, and the BCG vaccine has been shown to reduce the severity of infections by other viruses with that structure in controlled trials. ...whether BCG will be effective remains unknown: findings from the ecological studies suggesting less COVID-19 in countries with routine BCG immunisation are weak evidence because they are based on population rather than individual data and are prone to confounding.11 Also, it is unlikely that a BCG vaccine given decades ago in childhood will ameliorate COVID-19 now.
Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails ...to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.
The innate immune system is able to build memory-like features in response to certain infections or vaccines, resulting in enhanced responsiveness upon (re)challenge with the same or an unrelated ...pathogen, a phenomenon termed ‘trained immunity’. Compared with antigen-dependent adaptive immune responses triggered by classical vaccines against specific pathogens, trained immunity-related vaccines induce enhanced innate immune responses against unrelated pathogens and provide ‘heterologous protection’. Here, we discuss the heterologous effects of vaccines against infections and detail the latest insights into the cellular and molecular mechanisms mediating trained immunity. Additionally, novel vaccine strategies are suggested for fighting new pandemics in the future by taking advantage of the heterologous memory features of trained immunity.
Trained innate immune cells have improved antimicrobial function mediated by transcriptional and epigenetic rewiring. Long-lasting trained immunity is centrally regulated in hematopoietic progenitors in the bone marrow and peripherally induced in tissue-resident cells.Distinct trained immunity programs at the single cell level identify trained monocyte subpopulations.Heterologous or nonspecific protection of vaccines against unrelated pathogens can be partially explained by induction of trained immunity responses.BCG, MTBVAC, influenza, measles, and possibly the new mRNA Coronavirus 2019 (COVID-19) vaccines induce trained immunity signatures, while trained immunity inducers can act as vaccine adjuvants.Environmental factors, the microbiome, circadian rhythm, genetics, and sex influence vaccine-induced trained immunity heterogeneity.
Immunological memory is an important evolutionary trait that improves host survival upon reinfection. Memory is a characteristic recognized within both the innate and adaptive arms of the immune ...system. Although the mechanisms and properties through which innate and adaptive immune memory are induced are distinct, they collude to improve host defense to pathogens. Here, we propose that innate immune memory, or “trained immunity,” is a primitive form of adaptation in host defense, resulting from chromatin structure rearrangement, which provides an increased but non-specific response to reinfection. In contrast, adaptive immune memory is more advanced, with increased magnitude of response mediated through epigenetic changes, as well as specificity mediated by gene recombination. An integrative model of immune memory is important for broad understanding of host defense, and for identifying the most effective approaches to modulate it for the benefit of patients with infections and immune-mediated diseases.
In this Perspective, Netea et al. examine the distinct factors involved in innate immune memory (also termed trained immunity) and in the more advanced and specific adaptive immune memory. The authors then propose an integrative model of immune memory for a better understanding of the host defense system.
Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy ...is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.
Microorganisms in the human intestine (i.e. the gut microbiome) have an increasingly recognized impact on human health, including brain functioning. Attention-deficit/hyperactivity disorder (ADHD) is ...a neurodevelopmental disorder associated with abnormalities in dopamine neurotransmission and deficits in reward processing and its underlying neuro-circuitry including the ventral striatum. The microbiome might contribute to ADHD etiology via the gut-brain axis. In this pilot study, we investigated potential differences in the microbiome between ADHD cases and undiagnosed controls, as well as its relation to neural reward processing.
We used 16S rRNA marker gene sequencing (16S) to identify bacterial taxa and their predicted gene functions in 19 ADHD and 77 control participants. Using functional magnetic resonance imaging (fMRI), we interrogated the effect of observed microbiome differences in neural reward responses in a subset of 28 participants, independent of diagnosis.
For the first time, we describe gut microbial makeup of adolescents and adults diagnosed with ADHD. We found that the relative abundance of several bacterial taxa differed between cases and controls, albeit marginally significant. A nominal increase in the Bifidobacterium genus was observed in ADHD cases. In a hypothesis-driven approach, we found that the observed increase was linked to significantly enhanced 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase in cases relative to controls. This enzyme is involved in the synthesis of phenylalanine, a precursor of dopamine. Increased relative abundance of this functionality was significantly associated with decreased ventral striatal fMRI responses during reward anticipation, independent of ADHD diagnosis and age.
Our results show increases in gut microbiome predicted function of dopamine precursor synthesis between ADHD cases and controls. This increase in microbiome function relates to decreased neural responses to reward anticipation. Decreased neural reward anticipation constitutes one of the hallmarks of ADHD.
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and ...individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed “trained immunity,” by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Netea and colleagues argue that we may be able to prevent or decrease the severity of SARS-CoV-2 infection through certain clinically approved live vaccines that “train” the innate immune system to be broadly vigilant against viral infection.
Renewed interest in immune cell metabolism has led to the emergence of a research field aimed at studying the importance of metabolic processes for an effective immune response. In addition to the ...adaptive immune system, cells of the myeloid lineage have been shown to undergo robust metabolic changes upon activation. Whereas the specific metabolic requirements of myeloid cells after lipopolysaccharide/TLR4 stimulation have been extensively studied, recent evidence suggested that this model does not represent a metabolic blueprint for activated myeloid cells. Instead, different microbial stimuli, pathogens, or tissue microenvironments lead to specific and complex metabolic rewiring of myeloid cells. Here we present an overview of the metabolic heterogeneity in activated myeloid cells during health and disease. Directions for future research are suggested to ultimately provide new therapeutic opportunities. The uniqueness of metabolic signatures accompanying different conditions will require tailor-made interventions to ultimately modulate aberrant myeloid cell activation during disease.
The importance of intracellular metabolism in determining myeloid cell function has rapidly gained interest. In this review, Stienstra et al. discuss the current state of knowledge in the field of immunometabolism, revealing specific and complex metabolic rewiring in activated myeloid cells in health and disease.
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